The long-term objectives are to understand the neurobiological role of insulin-like growth factor I (IGF-I), and investigate the potential usefulness of IGF-I in the management of neurodegenerative disorders and trauma to the nervous system. The major specific aims of this Project are to test the inter-related hypotheses that IGF-I gene expression helps to regulate synaptogenesis in mammals during development, that IGF-I gene expression mediates synaptogenesis modulated by nerve-muscle use and disuse, that IGF-I gene expression contributes to peripheral nerve regeneration rates, and that IGF-I can accelerate motor and sensory axon regeneration rates. The IGF-I gene is among only a few gene presently suspected of instructing the development and regeneration of vertebrates synapses, and might be regarded as a prototype gene regulating the turnover of vertebrate synapses. The wealth of data and simplicity of the neuromuscular junction makes it an appropriate model. These studies will be done in rats, mice, and embryonic chicks. The mechanisms of nerve regeneration is currently understood primarily at a descriptive level, and the results of this Project will contribute much needed data concerned with the molecular processes underlying peripheral nerve regeneration. Furthermore, the results are likely to suggest new therapeutic interventions for promoting more rapid and complete peripheral nerve regeneration, and will provide new concepts and theories to be tested by those concerned with regeneration in the central nervous system. Further light will be shed as well on the potential involvement of these factors in neurodegenerative disorders, particularly those involving loss of synapses, axons and dendrites, and neurons, such as diabetic neuropathy.